This invention relates to the field of prevention of damage arising from spinal cord injury and trauma to the brain, including that which occurs secondary to decompression sickness (DCS).
At present, spinal injury, whether arising from trauma or disease, disables many Americans of all ages. There is need for means of effective treatment to prevent such disabilities.
Alpha lipoic acid (xcex1LA) is an antioxidant currently used clinically to treat diabetic neuropathy. It has been shown to be clinically safe and was shown to be neuroprotective against ischemia-reperfusion injury in both the rat and the gerbil. It was also effective against NMDA and malonic acid lesions of striatum in rats. However, its effects in preventing or ameliorating damage arising because of pathologies and trauma to the spinal cord or trauma-induced injury to the brain, including spinal cord injury secondary to decompression sickness (DCS), has not been known.
DCS-induced spinal injury is often associated with hemorrhage into the spinal cord. Extravasated hemoglobin releases iron, which is deposited in neural tissues where it is neurotoxic due to free radical formation and lipid peroxidation, resulting in cavitation and gliosis. The interaction with the superoxides and peroxides with cell membrane components can cause protein chain polymerization, destruction of sulfhydryl groups and degradation of DNA and amino acids. Hemoglobin has also been shown to potentiate excitatory amino acid-induced neurotoxic injury in cortical cell culture. There is need for agents which effectively protect against this pathological cascade.
Presently, post-injury treatment of spinal cord injury is most likely to include administration of the steroid methylprednisolone for 24 to 48 hours to reduce swelling and inflammation. In patients with accident-related acute spinal cord injury, clinical outcome at 6 months was improved in those receiving this steroid within eight hours of injury compared with placebo-treated patients. Unfortunately, there is some evidence that glucocorticoids (GC""s) can exacerbate the excitotoxic phase of neural injury. Postulated mechanisms of GC-mediated synergy with excitotoxic effects of glutamic acid include: (1) glucocorticoides inhibit reuptake inactivation of synaptic glutamic acid, thereby increasing synaptic glutamic acid levels and/or (2) glucocorticoids inhibit calcium removal from the postsynaptic neuron.
It is the purpose of this invention to provide means to prevent neuronal damage arising because of injury to the spinal cord or brain. The administration of xcex1-lipoic acid (xcex1LA) and dihydrolipoic acid (DHL) both as a preventive measure before exposure to conditions which may cause damage, such as rapid changes in atmospheric pressure, and as a means of preventing or ameliorating damage arising from such injury provides benefits not currently available. The active agents may be administered systemically or to the injured tissue. For example, when there is spinal cord injury, the active agents may be administered intrathecally.
There are many instances when an injury may not be immediately life-threatening, but may have potential to cause severe disability. Injuries such as those arising from penetrating injuries, exposure to blast, blunt trauma, falls and vehicular accidents as well as spinal cord and brain injury secondary to systemic phenomena such as decompression sickness are examples of instances when use of xcex1LA and dihydrolipoic acid in accord with the teachings of this disclosure would be appropriate. Conditions such as herniated discs or degenerative diseases such as amyotrophic lateral sclerosis and multiple sclerosis are pathological processes whose deleterious effects may be ameliorated by practice of the methods of the invention.
One great advantage associated with the use of xcex1LA is that it may be administered orally, is readily absorbed and is converted to the more potent neuroprotectant, dihydrolipoic acid. It is well tolerated in man and may be given prophylactically to soldiers at risk for spinal cord injury.
The use of xcex1-lipoic acid can be demonstrated for efficacy in preventing spinal cord injury using the following models: (1) Dynorphin-A induced ischemia, (2) animal models of spinal cord injury secondary to decompression sickness and (3) weight-drop models of spinal cord injury.
Since decompression sickness-induced spinal cord injury can be modelled by placing rats in a hyperbaric chamber, it is possible to use such a model to screen for clinically-available compounds which might mitigate risk in a vulnerable population. However, a model of spinal injury with less variability and higher throughput provides a more efficient way to test therapeutic concepts. The methods of the invention include prophylaxing against damage arising from spinal cord injury or pathology comprising administration of a neuronal protective amount of at least one agent chosen from among dihydrolipoic acid, xcex1-lipoic acid or an ester of xcex1-lipoic acid before exposure to circumstances which give rise to spinal cord injury. If damage has occurred, it is appropriate to treat the vertebrate who has incurred spinal cord or brain injury or pathology to prevent neuronal damage arising from said injury or pathology by administering a neuronal damage preventing effective amount of at least one agent chosen from among dihydrolipoic acid, xcex1-lipoic acid or an ester of xcex1-lipoic acid.